Organophosphate (OP) and carbamate pesticides and nerve agents and other agents are a significant threat to military personnel and civilians. In addition, farmers, agricultural workers and pesticide applicators handle large amounts of OPs and other agents and are exposed to these toxic materials. Between 150,000 and 300,000 OP-related human toxic incidences are reported annually in the United States (Lancet, 338: 223-227, 1991). Additionally, toxic organic compounds are present in industrial materials including jet fuel and other fuel and cause toxicity.
Some examples of toxic agents are that undergo metabolic oxidation to form active organophosphate, “Oxon”.
OP and carbamate pesticides and chemical warfare nerve agents and other electrophilic agents are potent covalent inhibitors of proteins and receptors including serine hydrolases including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) in the blood and in the central nervous system (CNS). In addition, these agents covalently modify other protetins. Examples of organophosphates include Sarin, Cyclosarin, Soman, Tabun, VX, Diazinon, DFP (2-(Fluoro-(1-methylethoxy)phosphoryl)oxypropane), Fenthion, Malathion, Parathion, Chlorpyrifos, and Echothiophate. Some examples of carbamates include Physostigmine, Neostigmine, Rivastigmine, Methiocarb, and Carbofuran.
Once covalently inhibited, the resulting OP- or carbamate-ChE adduct undergoes slow spontaneous hydrolysis and does not allow ChE to conduct its normal function to hydrolyze the neurotransmitter acetylcholine (ACh). Accordingly, ACh builds up in the synapse and stimulates autonomic receptors and blocks neuromuscular junction receptors. The symptoms resulting from toxic agent exposure are primarily the consequence of accumulation of excess ACh where ordinarily only small amounts of ACh are present at nerve junctions.
Currently, clinically available treatments for acute OP or carbamate poisoning include combined administration of a ChE reactivator (an oxime), a muscarinic receptor antagonist (atropine), and an anticonvulsant (diazepam). Oximes are antidotes for the poisoning and a clinically used drug is available (e.g., 2-PAM (Pralidoxime) containing an oxime group attached to a pyridinium quaternary center.